Pelitinib_DataSheet_MedChemExpress
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Inhibitors, Agonists, Screening Librarieswww.MedChemExpress.comData SheetBIOLOGICAL ACTIVITY: Pelitinib (EKB–569; WAY–EKB 569) is a potent irreversible EGFR inhibitor with IC50 of 38.5 nM.IC50 value: 38.5 nM [1]Target: EGFRin vitro: Pelitinib displays much higher inhibitory activity against EGFR, compared with the closely related c–erbB–2, as well as otherkinases such as Src, Cdk4, c–Met, Raf, and MEK/ERK, with IC50 ranging from 282 nM for Src to >20 μM for Cdk4. Consistently, Pelitinibtreatment significantly inhibits the autophosphorylation of EGFR but not c–Met in A431 cells [1]. Pelitinib potently inhibits theproliferation of normal human keratinocytes (NHEK), as well as A431 and MDA–468 tumor cells with IC50 of 61 nM, 125 nM, and 260nM, respectively, while displaying little activity against MCF–7 cells with IC50 of 3.6 μM. Pelitinib inhibits EGF–induced phosphorylationof EGFR in A431 and NHEK cells with IC50 of 20–80 nM, as well as the phosphorylation of STAT3 with IC50 of 30–70 nM. Pelitinib at75–500 nM also specifically inhibits the activation of AKT and ERK1/2, without affecting NF–κB pathway. In NHEK cells, Pelitinib alsopotently inhibits TGF–α mediated EGFR activation with IC50 of 56 nM, as well as activation of STAT3 and ERK1/2 with IC50 of 60 nMand 62 nM, respectively [2].in vivo: A single oral dose of 10 mg/kg Pelitinib potently inhibits the EGFR phosphorylation in A431 xenografts with over–expressedEGFR, by 90% within 1 hour, and by >50% after 24 hours. Administration of Pelitinib at 20 mg/kg/day inhibits tumorigenesis inAPCMin/+ mice by 87%, equivalent to the effect of used with 2 times doses of EKI–785 (40 mg/kg/day), consistent with greater in vivopotency [1]. Pelitinib selectively inhibits EGFR signaling in airway epithelial cells in vivo. In the mouse model of airway epithelialremodeling that is inducible by viral infection and features a delayed but permanent switch to goblet cell metaplasia, Pelitinibtreatment at 20 mg/kg/day corrects all 3 aspects of epithelial remodeling, by completely blocking the increase of ciliated cells anddecrease of Clara cells, and significantly inhibiting the metaplasia of goblet cells [3].PROTOCOL (Extracted from published papers and Only for reference) Cell assay [2]To determine the effect of EKB–569 on the growth of human tumor cell lines and NHEK cells, proliferation in 96–well dishes wasassessed using 3–(4,5–dimethylthiazol–2–yl)–2,5–diphenyltetrazolium bromide (MTT) assay as described previously (21). Forexperiments with A431, MCF–7, and MDA–468, 3 × 103 cells/well were seeded in 100 μl complete DMEM/10% fetal bovine serum forA431 and MDA–468 cells or complete improved MEM/20% fetal bovine serum for MCF–7 cells. For experiments with keratinocytes, 3× 103 cells/well were seeded in 100 μl complete keratinocyte growth medium. After 2 h, EKB–569 was added in 100 μl (0.001–10 μM)in triplicate and incubated at 37°C. After incubation for 5 days, the medium was removed from each well and fresh medium (150 μl) +1 mg/ml MTT solution (50 μl) was added. After incubation for 2 h at 37°C, the medium was replaced with 150 μl DMSO, andabsorbance at 540 nm in each well was determined. The IC50 was calculated by linear regression of the data.Product Name:PelitinibCat. No.:HY-32718CAS No.:257933-82-7Molecular Formula:C24H23ClFN5O2Molecular Weight:467.92Target:EGFR; EGFRPathway:JAK/STAT Signaling; Protein Tyrosine Kinase/RTKSolubility:DMSO: 16 mg/mL
www.MedChemExpress.comReferences: [1]. Torrance CJ, et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med, 2000, 6(9), 1024–1028.[2]. Nunes M, et al. Phosphorylation of extracellular signal–regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3are differently inhibited by an epidermal growth factor receptor inhibitor, EKB–569, in tumor cells and normal human keratinocytes. Mol Cancer Ther, 2004,3(1), 21–27.[3]. Tyner JW, et al. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL–13 transdifferentiation signals. J Clin Invest, 2006, 116(2),309–321.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@MedChemExpress.comAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA
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